Tunable CTPhos and Chloride Enabled Direct Asymmetric Reductive Amination for the Synthesis of Chial Hydroxylamines

Abstract

Chiral hydroxylamines are important structural motifs and intermediates for a variety of drugs and bioactive molecules. Herein we report the first example of direct asymmetric reductive amination for the direct synthesis of N-H and N-alkyl chiral hydroxylamines. By utilizing complexes generated in situ from a neutral Ir(I) precursor and highly tunable CTPhos ligands as catalysts, we demonstrate that a selection of ketones can be reductively coupled with two types of hydroxylamine nitrogen sources to yield the corresponding chiral products in high yields and enantiomeric excesses, thereby eliminating the need to isolate and use (E)-isomers of oxime intermediates. The series of highly modulated and easily programmable CTPhos ligands promise a suitable enantio-environment for these reactions. Additionally, the chloride atom plays vital roles in the hydrogen addition step by forming a pair of hydrogen bonds among the catalytic species, hydroxylamine, and the protonated oxime intermediate. The H-bonding and other noncovalent interactions stabilize the key transition state and enable high enantioselectivity.